In recent years, antibiotic resistance has evolved dramatically and is now classified as the next pandemic.1 As i life-threatening infections due to multi-resistant (MDR) pathogens are rising, the discovery of novelmolecules is key to contribute at solving this pressing issue.2 However, the diversity of natural sourcesexplored by scientists in the last century limits the prospects of finding novel molecular scaffolds. Our research process combines a new, powerful, and open source dereplication application (OctoChemDB) with a classic bio-assay-guided fractionation applied on unprecedented fungi from different ecosystems and extremophiles. Briefly, extracts of these unexplored organisms were fractionated by solid-phase extraction and reversed-phase HPLC. Active fractions against MDRpathogens were purified to single products and characterized by High-Resolution Mass Spectrometry (HRMS) analysis. OctoChemDB, which is a browser application that compiles main chemistry databases, is able to sort out bioactive molecules corresponding to the purified analyte. This allows to rapidly identify known antibiotics and dereplicate them to maximize chances of finding novel molecules. Altogether, we managed to significantly accelerate the natural products discovery process: six known antibiotics with activity against MDRisolates were successfully dereplicated from 7 organisms not known to produce these compounds, including Cephalochromin
Discovery of Novel Antimicrobials from Unexplored Natural Sources as Novel Agents Against Multidrug-Resistant Pathogens
Federica Spina;Davide Ferrero;Giovanna Cristina Varese;
2023-01-01
Abstract
In recent years, antibiotic resistance has evolved dramatically and is now classified as the next pandemic.1 As i life-threatening infections due to multi-resistant (MDR) pathogens are rising, the discovery of novelmolecules is key to contribute at solving this pressing issue.2 However, the diversity of natural sourcesexplored by scientists in the last century limits the prospects of finding novel molecular scaffolds. Our research process combines a new, powerful, and open source dereplication application (OctoChemDB) with a classic bio-assay-guided fractionation applied on unprecedented fungi from different ecosystems and extremophiles. Briefly, extracts of these unexplored organisms were fractionated by solid-phase extraction and reversed-phase HPLC. Active fractions against MDRpathogens were purified to single products and characterized by High-Resolution Mass Spectrometry (HRMS) analysis. OctoChemDB, which is a browser application that compiles main chemistry databases, is able to sort out bioactive molecules corresponding to the purified analyte. This allows to rapidly identify known antibiotics and dereplicate them to maximize chances of finding novel molecules. Altogether, we managed to significantly accelerate the natural products discovery process: six known antibiotics with activity against MDRisolates were successfully dereplicated from 7 organisms not known to produce these compounds, including Cephalochromin
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